Both genetic and environmental contributions have crucial roles in the development of a complex disease such as alcoholism. Unfortunately, little progress has been made in identifying the underlying molecular mechanisms altered during abstinence to aid development of novel therapeutics for the maintenance of sobriety. We propose a combined genetic, molecular, pharmacological and behavioral strategy to identify pathways that are altered after a period of abstinence. Neuroadaptations in brain structure, plasticity and gene expression occur with chronic alcohol abuse, but the stability of these expression differences in the abstinent alcoholic is controversial. We have previously reported identification of pathways altered in prefrontal cortex (PFC), a brain region associated with cognitive dysfunction and damage in alcoholics, during a defined period of abstinence. To characterize genetic contributions, both sexes of an animal model with widely divergent responses to alcohol derived by selective breeding, the Withdrawal Seizure-Resistant (WSR) and Withdrawal Seizure-Prone (WSP) lines, were analyzed. During a sustained period of abstinence, the transcriptional response correlated with withdrawal phenotype rather than sex. Bioinformatic analysis showed that among the major pathways altered that were the most dimorphic between WSR and WSP mice were 'acetylation' and 'histone deacetylase complex'. Data shows a complex phenotype-specific regulation during abstinence indicating widespread epigenetic reprogramming in the low response WSR but not the high response WSP mice exposed to the same ethanol concentrations. We will identify phenotype-specific regulatory mechanisms in the low response animal model in three specific aims by integrating data from high-throughput targeting technologies including expression profiling, DNaseI-seq and ChIP-seq, with confirmation of involvement of pathways to modulate relapse using pharmacological intervention in our established dependence-induced relapse drinking model. We hypothesize that targetable epigenetic mechanisms maintain expression differences during abstinence and that these differences increase the risk of relapse in the low response to alcohol endophenotype. These studies have high impact because of the morbidity/mortality associated with alcohol abuse, the high incidence of alcohol use disorders in the general population, and the tremendous impact these maladies have on human health. In addition, neuroadaptive changes and altered expression patterns may also play a role in persistent neurotoxicity and brain damage during abstinence with detrimental consequences for learning and memory functions, to play a role in the down-ward cycle of addiction and the self-sustaining nature of alcoholism. Thus, successful completion of these aims will aid in our understanding of the mechanism(s) underlying the risk for relapse and advance our ability to provide therapy for alcohol abuse targeted to the low response endophenotype, through identification of novel pharmacotherapies or to enhance translational applications for currently available therapeutics with previously unrecognized utility.